Adenosine A2A receptors (also known as ADORA2A) are members of the G protein-coupled receptor (GPCR) family which possess seven transmembrane alpha helices. The receptor is mediated by G proteins, which activate adenylyl cyclase and is abundant in basal ganglia, vasculature and platelets and is a major target of caffeine. The A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. The A2A receptor is also expressed in the brain, where it has important roles in the regulation of glutamate and dopamine release. The A2A receptor signals in both the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists as useful in neurodegenerative disorders such as Parkinson's disease.
Despite the increasing development of adenosine A2A receptor agonists, as described above, only one, regadenoson, an adenosine analog, has been approved for use in the United States as a coronary vasodilator. Typical issues involved with administration of these compounds include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, and/or a lack of effects, in some cases possibly due to receptor desensitization or too low receptor density in the targeted tissue. Therefore, it is important to continue to synthesize and test additional A2A receptor agonists in order to develop new and improved therapeutic agents.